N-(diarylmethyl)-tertiary-aminoalkanamides and their preparation



Patented Aug. 29, 1950 UNITED STATES PATENT OFFICE N (DIARYLMETHYIJ)TERTIARY AMINO- ALKANAMIDES AND THEIR PREPARATION Elmer J. Lawson, EastGreenbush, George M.

Fohlen, Albany, and Aaron Addelston, Flushin g, N. Y., assignors toSterling Drug Inc., Wilmmgton, Del., a corporation of Delaware NoDrawing. Application September 11, 1947, Serial No. 773,520

16 Claims. (Cl- 260 -294) BYCON (R) CH (A) (A1) wherein B is analiphatic tertiary-amino group, Y is a lower alkylene group, R is H or alower alkyl group, and A and A1 are aryl groups, exhibit valuabletherapeutic properties, such as local anesthetic activity. In the aboveformula, the aliphatic tertiary-amino group designated as B is a groupsuch as diethylamino, dimethylamino, methylethylamino, di-n-butylamino,l-piperidyl, 2-methyl-1-piperidyl, 4-morpholinyl, 2-methyll-pyrrolidyl,or the like. The lower alkylene group designated as Y is a group such asCH2, CH2CH2, CHzCHzCI-Iz, CI-I(CH3), CH(C2H5), C(CzHs) 2, CH2CH(CH3)CH2C(CH3) 2, or the like. The lower alkyl group R is a group such asmethyl, ethyl, n-propyl, Z-propyl, n-butyl, or the like. A and A1 may beeither unsubstituted phenyl or phenyl groups substituted by groups whichare unreactive to acid halides. Such substituent groups include thefollowing: alkoxyl, such as methoxyl, ethoxyl, and the like; loweralkyl, such as methyl, ethyl, Z-butyl, and the like; dialkylamino, suchas diethylamino, dimethylamino, and the like; and halogen, such aschlorine, bromine or iodine. A and A1 can be the same or different andcan be linked to each other in ortho-positions, either directly to formthe fiuorene ring or through a bridge involving such elements as carbon,nitrogen, oxygen, and sulfur to form the rings of9,10-dihydroanthracene, acridan, xanthene and thiaxanthene respectively.A few specific examples of compounds that come within the scope of ourinvention include the following:N-benzohydryl-2-dimethylaminoethanamide,

(CH3) 2NCH2CONHCH(C6H5) 2 N-benzohydryl-3-diethylaminopropanamide,

(CzHs) 2NCH2CH2CONHCH(C6H5) z N -(bis(4 methoxyphenyDmethyD- 4 -(1piperidyl) butanamide,

0112-031 @oom c 1 N-cmomcmoomzc cm-o 2 OCH:

2 N benzohydryl N ethyl 3 di -41 butylamino-Z-methyIpropanamide,

N -(9 fiuorenyl) 3 -(2 methyl 1 piperidyl) propanamide,

CHz-CH-CH:

C 2 N-CHzCHlC ONHCH N -(bis(3 ethoxyphenyDmethyD- 3 -(4 morpholinyl)butanamide,

N- (9-xanthyl) -2- diethylaminoethanamlde,

N-9- (9,10-dihydroanthryl) -3-dimethylaminopropanamide,

and the like.

The compounds of our invention can be prepared by various means. Onemethod of preparation involves treating an (aliphatic tertiaryamino)alkanoyl halide with the appropriate diarylmethylamine or (loweraIkyDdiaryhnethylamine; for example, treating 3-diethylamino-2,2-diethylpropanoyl chloride with 9-iiuorenylamine ormethylbenzohydrylamine to yield respectively N -(9 fluorenyD- 3diethylamino 2,2 diethylpropanamide hydrochloride or N-(benzohydryl) Nmethyl 3 diethylamino 2,2 di- IJIOJ.

ethy following respective equations:

l (cmomcmcw-no-oomso CI OsNOHrO (CiHdrG 001 KN(CH;) OH(Cs s)l e(CsHrhNOHrIXCsHOICONKCIh) CH(C|H|)| OCs -s OIOKIOHIOOO! KsNC eOlCBsOHsOONHO w cm 011mm! (OHOINOHIC Hi0 ONHO Another method that can beused to prepare the N-diarylmethyl-tertiary-aminoalkanamides of ourinvention comprises reacting a lower alkyl ester of atertiary-aminoalkanoic acid with a diarylmethylamine. This method isillustrated by the following reaction between methyl3-dimethylaminopropanoate and benzohydrylamine:

In the last two mentioned processes the correspondingN-diarylmethyl-N-(lower alkyD-(aliphatic tertiary-amino) alkanamides areprepared if the diarylmethylamines used above are substituted bycorresponding (lower alkyl) diarylmethylamines.

It is often convenient to isolate and use the basic amides of ourinvention as the water-soluble hydrochloric acid addition salts. It is,of course, understood that other water-soluble salts, such as thosederived from other non-toxic inorganic acids, including hydrobromicacid, sulfuric acid, phosphoric acid, and the like, and non-toxicorganic acids, including tartaric acid, citric acid, succinic acid, andthe like will serve s '4 lpropanamidehydroehlorideasshowninthethessmepurpeseandarewithinthesecpecfour invention.

The following examples illustrate specinc embodiments of the invention.It is to be understood that the invention is not limited thereto butonly by the scope of the appended claims.

lv-bensohydul-i-diethylaminopropanamide hydrochloride A solution oi 9.2s. of N-benzohydryl-3-chloropropanamide and 12.2 g. (1'! ml.) ofdiethylamine in 100 ml. of benzene plus a few ml. of ethanol is refluxedfor one hour. Then the benzene solution is cooled, washed with water,and dried, either with anhydrctu sodium carbonate or by removal of somebenzene by distillation. After a volume or two of dry ether has beenadded to the resulting dry solution, the ether-benzene solution istreated with alcoholic hydrogen chloride whereupon a white, crystallineprecipitate eparates. A sample recrystallized from ethanol melts about182-3 C. This product is N-benzohydryl-Ii-diethylaminopropanamidehydrochloride of the formula (QIHDQNOHICHIC omzomcam.

The above starting material, N-bensohydryl- 3-chloropropanamide, whichmelts at 176 0., is prepared readily by carefully mixing a benzenesolution of benzohydrylamine with 3-chloropro- OOi s Da 's (OHdsNH-HOIpanoyl chloride in the presence of pyridine at 0' C. and stirring theresulting mixture about (CsHdsNC-HsOHaC ONHC The N-(Q-iiuorenyl)-3-chloropropanamide is prepared from Q-fluorenylamine and3-chloropropanoyl chloride according to the above directions given forthe preparation of N-bensohydryl- 3'-chloropropanamide.

Further, when the above procedure is carried out usingN-benzohydryl-N-methyl-s-chloropropanamide instead ofN-benzohydryl-S-chloropropanamide, the product obtained isN-benzohydryl-N-methyl 3 diethylaminopropanamide hydrochloride of theformula The intermediate N-benzohydrylN-methyl-S- chloropropanamide isprepared from methylbenzohydrylamine (See Busch and Leefhelm, J. pr.Chem. 77, -4 (1908), for the preparation of methylbenzohydrylamine) and3-chloropropanoyl chloride according to the above directions given forthe preparation of N-benzohydryl-tichloropropanamide.

EXAMPLE 2 N benzohydryl-Ii- (1 piperidyl) propanamide hydrochloride Asolution of 9.2 g. of N-benzohydryl ii-chloropropanamide and 14.3 g. ofpiperidine in 200 ml. of benzene is refluxed for one hour on a steambath. The reaction mixture is cooled and the piperidine hydrochloridewhich separates is removed by filtration. After the filtrate has beenwashed with water, about an equal volume of ether is added and theresulting ether-benzene solution is dried over anhydrous sodiumcarbonate. Addition of a solution of hydrogen chloride in alcohol to thedried solution causes precipitation of a white flaky crystallinematerial, which is filtered, washed with ether, and airdried.Recrystallization of this crystalline material from'ethanol yields thedesired product, N-benzohydryl-B- l-piperidyl) propanamidehydrochloride, melting about 217 C. and having the formula CHr-CH: oh,NoH=cH,ooNHcH c.Hm

CHzO 2 1 If morpholine is substituted for piperidine in the aboveexample, the corresponding N-benzohydryl-3- (4-morpholinyl) propanamidehydrochloride, melting about 203 C., and having'the following formula,is obtained:

When Z-methylpiperidine is used in place of piperidine, thecorresponding N-benzohydryl-S- (2-methyl-1-piperidyl)propanamidehydrochloride, of the following formula, is obtained:

CHr-CH-CH;

C i N-CH!CHQCONHCH(CQHI)I CHr-C I HCl EXANIPLE 3N-benzohydryl-3-dimethylaminopropanamide hydrochloride A solution of 9.2g. of N-benzohydryl-ii-chloropropanamide and 15 ml. of aqueousdimethylamine solution in 50 ml, of ethanol is refluxed for threehourson a steam bath. The reaction mixture is cooled and poured into 600ml. of water, and the resulting aqueous solution is extracted withbenzene. The benzene extract is washed with water, dried over anhydroussodium carbonate, and treated with a slight excess of alcoholic hydrogenchloride. After addition of about 800 ml. of ether, there separates awhite, sticky precipitate, which completely solidifies when placed in anice bath. Recrystallization of this solid from dioxane gives theproduct, N- benzohydryl 3 dimethylaminopropanamide hydrochloride,melting at 163-4 C, and having the formula:

When N-bis (3-ethoxyphenyl) methyl-3-chloropropanamide is used insteadof N-benzohydryl- 3-chloropropanamide, N bis(3 ethoxyphenyl) methyl 3dimethylaminopropanamide hydrochloride, having the following formula, isformed:

(CHa)zNCH2CH2C ONHCH EXAMPLE 4:

N beneohydryl-Z-diethylaminoethanamide hydrochloride This preparation iscarried out like Example 1, but using 8.7 g. ofN-benzohydryl2-chloroethanamide, 17 ml. of diethylamine, ml. of benzene,and a defluxing period of two hours. The product, Nbenzohydryl2diethylaminoethanamide hydrochloride, melts about 173-5 C.after recrystallization from isopropanol, and has the formula(CaHQzNCHaO ONHCH(Ca s):

HCl

The above starting material, N-benzohydryl- 2-chloroethanamide, whichmelts at 128 C., is prepared from benzohydrylamine and chloroacetylchloride in the presence of pyridine, according to the directions givenfor the pre aration of N -benzohydryl3-chloropropanamide 'mder Example1.

We claim:

1. A member of the group consisting of a basic amide having the formulaB-YCO--N(R) CH(A) (A1) where B is a di(lower alkyl) amino group attachedto Y through its nitrogen atom and wherein the alkyl groups may bejoined to form a member of the group consisting of piperidines,morpholines and pyrrolidines and Y is a lower alkylene group, and acidaddition salts thereof.

3. A member of the group consisting of N- benzohydryl 3diethylaminopropanamide and acid addition salts thereof.

assume 4.Amemberofthegroupof1fbensohydryl 3 (i-piperi yvpropanamtde andacid addition saltsthereof.

asmemberorthegroupcomisfl sofflbensohydryi-Z-diethylaminoethanamide andacid addition salts thereof.

0. Aprocessofpreparingabasicamidehaving the formula where B is adi(lower alkyl) amino group attached to Y through its nitrogen atom andwherein the alhlir p maybeloinedtoformamemberof the group consisting ofpiperidines, morpholines and pyn'oiidines, Y is a lower aikyiene group,R is a member of the group consisting of hydrogen and a lower alkylgroup, and A and A1 are 817] groups of the benzene series, whichcomprises treating a compound having the formula halogen--YCON(R)CH(A)um with a secondary amine having the formula 8H.

7. The process of preparing a basic amide having the formulan-r-co-Nn-cmcdn):

where B is a di(lower albl) amino group attached to Y through itsnitrogen atom and wherein the albl groups may be Joined to form a memberof the group consisting of piperidines, morpholines and pyrrolidines andY is a lower alkylene group, which comprises treating a compound havingthe formula 119108 en-Y-CONHCH( Com) 2 (lower alkyl) 2N-YCONHCH CeHs)wherein Y is a lower alhlene group, and acid addition salts thereof.

8 12. Amemberofthegroupconsistingofabasic amidehavingtheformula whereinY is a lower alkylene group, and acid addition salts thereof.

13. The process of preparing a basic. amide having the formula (loweralrynm-r qo-nn-cmctmn wherein Y is a lower alkyfene group, whichcomprises treating a compound having the formula halogen-YCONH'CH(Cells) 2 with a secondary amine having the formula (lower alkyDzNH.

14. The process of preparing a basic amide having the formula V CHr-OH:

o I NY-CO-NBCH(COHO9 CHr-C 1 wherein Y is a lower alkylene group, whichcomprises treating a compound having the formula with piperidine.

15. A member of th group consisting of N-benzohydryl-3-dimethylaminopropanamide and acid addition salts thereof.

16. The process of preparing N-benzohydryl- 3-dimethylaminopropanamidewhich comprises treating N-benzohydryl 3 chioropropanamide withdimethylamine.

- ELMER J. LAWSON.

GEORGE M. FOHLEN. AARON ADDELSTON.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,073,100 Eisleb Mar. 9, 19372,126,329 Heifer Aug. 9, 1938 2,139,190 Iselin et a1 Dec. 9, 19382,153,707 Becherer et a1 Apr. 11, 1939 2,258,721 Sallman Oct. 14, 19412,326,497 Riester et a1 Aug. 10, 1943 2,356,587 Hentrich et a1 Aug. 22,1944 2,411,662 Martin et a1 Nov. 26, 1946 2,449,638 Bruce et a1 Sept.21, 1948

1. A MEMBER OF THE GROUP CONSISTING OF A BASIC AMIDE HAVING THE FORMULA